Table 3.

Summary of COVID-19 therapy studies: Existing broad-spectrum antiviral drugs

No	Drug/treatment	Author	Year	Study aim	Study type	Study design	Status	Main findings	Limitations
1.	Lopinavir, ritonavir, ribavirin	Cao et al [57].	2020	To evaluate the efficacy and safety of oral lopinavir–ritonavir for SARS-CoV-2 infection	Randomised, controlled, open label clinical trial.	199 laboratory-confirmed COVID-19 patients randomised at a 1:1 ratio into lopinavir-ritonavir in addition to standard care (n = 99) and standard care alone (n = 100) groups.	Ongoing	Treatment with lopinavir–ritonavir was not associated with a difference from standard care in the time to clinical improvement (HR = 1.31, 95% CI = 0.95-1.80]). Mortality at 28 d was similar between the groups (19.2% vs 25.0%; difference, -5.8 percentage points; 95% CI = 17.3-5.7).	Based on preliminary data. Lopinavir–ritonavir treatment was stopped early in 13 patients (13.8%) because of adverse events. Possible that knowledge of the treatment assignment might have influenced clinical decision-making.
		Horby et al [58]	2020	To report the results of a randomised trial to assess whether lopinavir– ritonavir improves clinical outcomes in patients admitted to hospital with COVID-19	Open-label, platform RCT	5040 patients from 176 UK sites from randomly assigned 1:2 to receive lopinavir-ritonavir plus standard care (400mg and 100mg) (n = 1616) or standard care alone (n = 3424).	Complete	Treatment does not improve clinical outcome. 374 (23%) of lopinavir–ritonavir patients and 767 (22%) usual care patients died within 28 d (RR 1.03, 95% CI = 0.91-1.17; P = 0.60). No significant difference in time until discharge alive from hospital (median 11 d [IQR 5 to >28] in both groups) or the proportion of patients discharged from hospital alive within 28 d (RR = 0.98, 95% CI = 0.91-1.05; P = 0.53)	No information collected on non-serious adverse effects or biomarkers. Few intubated patients included so unable to access effectiveness on critical patients.
2.	Interferon (IFN)	Davoudi-Monfared et al [59]	2020	To evaluate the efficacy and safety of IFN-β 1a in patients with severe COVID-19	Randomised clinical trial	81 patients randomised to treatment with IFN-β 1a (n = 42) or control (n = 39).	Complete	Time to the clinical response was not significantly different between the IFN and the control groups (P = 0.95). On day 14, 66.7% vs 43.6% of patients in the IFN group and the control group were discharged (OR = 2.5; 95% CI = 1.05 to 6.37). The 28-d overall mortality was significantly lower in the IFN than the control group (19% vs 43.6%, respectively, P = 0.015).	Some COVID-19 cases were not confirmed by PCR, patients’ stage of disease not accurately classified.
		Monk et al [60]	2021	To determine whether inhaled SNG001 has the potential to reduce the severity of lower respiratory tract illness and accelerate recovery in patients diagnosed with COVID-19.	Phase 2, double-blind, placebo-controlled, RCT.	98 patients from 9 UK sites randomly assigned 1:1 to the treatment group (n = 48) and placebo (n = 50). Treatment was administered by inhalation for 14 d.	Ongoing	Patients receiving SNG001 had greater odds of improvement (OR = 2.32 95% CI = 1-07-5.04]; P =  · 033) on day 15 or 16 and were more likely than those receiving placebo to recover to an OSCI score of 1 (no limitation of activities) during treatment (HR 2.19. 95% CI = 1.03-4 = 69; P =  · 043). SNG001 was well tolerated.	Pilot study, limited sample size, nebuliser unsuitable for patients requiring ventilation. 6 patients withdrew from treatment group and 5 from placebo group.
		Rahmani et al [61]	2020	To assess the efficacy and safety of IFN β-1b in the treatment of patients with severe COVID-19	Open-label, randomised clinical trial	66 patients from one site were randomised at a 1:1 ratio into the treatment (n = 33) and the control group (n = 33) for 2 weeks.	Complete	Time to clinical improvement in the IFN group was significantly shorter than the control group (9 d vs 11 d respectively, P = 0.002, HR = 2.30; 95% CI = 1.33–3.39]). At day 14, there was a lower percentage of discharged patients (78.79% vs 54.55) (OR = 3.09; 95% CI = 1.05-9.11, P = 0.03). ICU admission rate in the control group was significantly higher than the IFN group (66.66% vs 42.42%, P = 0.04 All-cause 28-d mortality was 6.06% and 18.18% in the IFN and control groups respectively (P = 0.12).	The effect of IFN on viral clearance was not determined. Small sample size.
		Hung et al [62].	2020	To assess the efficacy and safety of combined interferon beta-1b, lopinavir–ritonavir, and ribavirin for treating patients with COVID-19.	Multicentre, prospective, open label, randomised, phase 2 trial.	127 patients with RT-PCR confirmed COVID-19 randomised at a 2:1 ratio to treatment with combination of lopinavir, ritonavir, ribavirin and IFN (n = 86) and lopinavir and ritonavir (n = 41) groups.	Complete	The combination group had a significantly shorter median time from start of study treatment to negative nasopharyngeal swab (7 d, IQR 5–11) than the control group (12 d, IQR = 8-15; HR = 4.37, 95% CI = 1.86-10.24). Adverse events included self-limited nausea and diarrhoea with no difference between the two groups.	Trial was open label, without a placebo group, and confounded by a subgroup omitting IFN beta-1b within the combination group, depending on time from symptom onset. Study did not include critically ill patients.
3.	Corticosteroids	Zhang et al [36].	2020	To study the epidemiology, clinical features, and short-term outcomes of patients with COVID-19 in Wuhan, China.	Single centre, retrospective, case series study.	Data of 221 laboratory-confirmed COVID-19 patients were analysed for epidemiological, clinical, laboratory and radiological features, treatments, and outcomes.	Complete	A total of 64 (49.6%) patients were given glucocorticoid treatment. The severely affected patients receiving antiviral therapy:50 (90.0%) vs 146 (88.0%); P < 0.001) and glucocorticoid treatment: 40 (72.7%) vs 75 (45.2%); P < 0.001) were significantly higher than those patients who were not severely affected.	Most patients remain hospitalised.
		Liu Y. et al [63].	2020	To describe the clinical features, treatment, and mortality according to the severity of ARDS in COVID-19 patients.	Single centre, retrospective, cohort study.	Data of 109 laboratory-confirmed COVID-19 patients were analysed for differences in the treatment and progression with the time and severity of ARDS.	Complete	Patients with moderate to severe ARDS were the most likely to receive glucocorticoid therapy (P = 0.02) and high-flow nasal oxygen ventilation (P < 0.001). No significant effect of antivirus, glucocorticoid, or immunoglobulin treatment was found on survival in COVID-19 patients with ARDS (all log-rank tests P > 0.05).	Retrospective study, possibility for systematic selection bias.
		Liu T. et al [64].	2020	To explore changes of markers in peripheral blood of severe COVID-19 patients.	Single centre, retrospective, cohort study.	Data of 69 patients with severe COVID-19 were analysed for clinical characteristics and laboratory examination. 11 non-severe COVID-19 patients were included for comparison.	Complete	The higher level of IL-6 related to glucocorticoids (correlation coefficient [r] = 0.301, P = 0.001), human immunoglobulin (r = 0.147, P = 0.118), high flow oxygen inhalation (r = 0.251, P = 0.007), ventilator therapy (r = 0.223, P = 0.017).	Small sample size, retrospective study.
		Zhou et al [65].	2020	To explore risk factors of in-hospital death for patients and describe the clinical course of symptoms, viral shedding, and temporal changes of laboratory findings during hospitalisation.	Multi centre, retrospective, cohort study.	Data of 191 patients with laboratory-confirmed COVID-19 were analysed	Complete	Systematic corticosteroid and intravenous immunoglobulin use differed significantly (P = 0.0005) between non-survivors (n = 26; 48%) and survivors (n = 31; 23%).	Some laboratory tests not done in patients, underestimating effects on mortality. Small sample size.
		Tobaiqy et al [66].	2020	To retrospectively evaluate the therapeutic management received by patients with COVID-19 since emergence of the virus.	Systematic review.	41 studies (total 8806 patients) included in review after searching databases Embase, MEDLINE, and Google Scholar.	Complete	Corticosteroid treatment was reported most frequently (n = 25), despite safety alerts issued by WHO and CDC, followed by lopinavir (n = 21) and oseltamivir (n = 16).	Most studies included in the review were of low quality, with incomplete or inconsistent information on study design and outcome.
		WHO REACT working group [67].	2020	To evaluate the 28-d mortality associated with administration of corticosteroids compared with usual care.	Meta-analysis review.	Data of 1703 critically ill patients were pooled from 7 randomized clinical trials that evaluated the efficacy of corticosteroids.	Complete	Administration of dexamethasone (OR = 0.64) and hydrocortisone (OR = 0.69) for critically ill patients lowered the 28-d mortality rate.	The primary meta-analysis was weighted heavily by the RECOVERY trial (57% contribution). One of the studies included may have been subject to bias.
		RECOVERY collaborative group [68].	2021	To report the results of the RECOVERY trial of dexamethasone in hospitalised COVID-19 patients.	Open label RCT.	6425 patients randomised with a 2:1 ratio to dexamethasone (n = 2104) and usual care (n = 4321) groups.	Complete	482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 d after randomization (age-adjusted RR = 0.83; 95% CI = 0.75–0.93; P < 0.001).	Based on early findings.
4.	Drugs targeting the cytokine storm	Cantini et al [69].	2020	To evaluate the clinical impact and safety of Baricitinib therapy for patients with COVID-19.	Pilot study	24 consecutive patients with moderate symptoms were assigned at a 1:1 ratio to baricitinib with ritonavir-lopinavir (n = 12) and control based on ritonavir-lopinavir with hydroxychloroquine (n = 12).	Ongoing	Discharge at week 2 occurred in 58% (7/12) of the baricitinib-treated patients vs 8% (1/12) of controls (P = 0.027). At discharge, 57% (4/7) had negative viral nasal/oral swabs.	Pilot study based on early findings. Open label design. No randomisation. Lack of a proper control.
		Bronte et al [70]	2020	Investigate whether baricitinib-induced changes in the immune landscape are associated with a favourable clinical outcome for patients with COVID-19–related pneumonia.	Observational, longitudinal trial.	Of 86 hospitalised patients with COVID-19 related pneumonia, 20 patients received treatment while 56 patients were considered the control	Complete	patients treated with baricitinib had a marked reduction in serum levels of IL-6, IL-1β, and TNF-α, a rapid recovery of circulating T and B cell frequencies, and increased antibody production against the SARS-CoV-2 spike protein	Missing data for some outcomes, short follow-up time, not double-blinded, insufficient evidence to show immune-suppressive features.
		Cao Y. et al [71].	2020	To evaluate the efficacy and safety of ruxolitinib, a JAK1/2 inhibitor, for patients with COVID-19.	Multicentre, prospective, single-blind phase 2 RCT.	43 COVID-19 patients randomised at a 1:1 ratio into ruxolitinib plus standard-of-care (n = 22) and placebo based on standard-of-care treatment (n = 21) groups.	Ongoing	Treatment with ruxolitinib plus standard-of-care was not associated with significantly accelerated clinical improvement in COVID-19 patients (12 (IQR, 10-19) days vs 15 (IQR, 10-18) days; log-rank test P = 0.147; HR = 1.669; 95% CI = 0.836-3.335), although ruxolitinib recipients had a numerically faster clinical improvement.	Based on early findings. Small sample size. Patients insisted on nasal cannula oxygen until discharge, which may contribute to the non-statistically significant P value of clinical improvement.
		Roschewski et al [72].	2020	To reduce inflammation and improve clinical outcome of patients with severe COVID-19 by administering acalabrutinib, a highly specific inhibitor of Bruton tyrosine kinase (BTK) for the treatment of lymphoid malignancies.	Prospective, off-label clinical study.	19 hospitalised patients with confirmed COVID-19 and evidence of inflammation and/or severe lymphopenia.	Complete	Among 11 patients in the supplemental oxygen cohort, the median duration of follow-up from the initiation of acalabrutinib treatment was 12 (range, 10 to 14) days. All but one patient received at least 10 d of acalabrutinib, which was the anticipated treatment duration. At the time of formal data collection, eight (73%) patients no longer required supplemental oxygen and had been discharged from the hospital. Among 3 patients still requiring oxygen, one was on 4 L/min by nasal cannula and one was on a ventilator, both with decreasing oxygen requirements, Findings suggest BTK is a likely instigator for the pathological inflammatory response in severe COVID-19.	Findings based on an initial clinical study which has led to a confirmatory international prospective RCT.
		Huet et al [73].	2020	To assess the off-label use of anakinra in patients who were admitted to hospital for severe forms of COVID-19 with symptoms indicative of worsening respiratory function.	Retrospective cohort study.	52 consecutive patients were included in the anakinra group and 44 historical patients were identified in the Groupe Hospitalier Paris Saint-Joseph COVID cohort study for comparison.	Complete	Admission to ICU for invasive mechanical ventilation or death occurred in 13 (25%) patients in the anakinra group and 32 (73%) patients in the historical group (HR = 0.22, 95% CI = 0.11-0.41; P < 0.0001). The treatment effect of anakinra remained significant in the multivariate analysis (HR = 0.22, 95% CI = 0.10-0.49]; P = 0.0002). An increase in liver aminotransferases occurred in 7 (13%) patients in the anakinra group and 4 (9%) patients in the historical group.	The historical group differed sizeably from the anakinra group for several potentially confounding variables. Obesity was more frequent in the historical group and might have worsened the effects of SARS-CoV-2. In the multivariate analysis of the data, this comorbidity, as well as other between-group differences, did not affect the estimated effect of anakinra on the outcome
		Balkhair et al [74]	2020	To evaluate the efficacy of anakinra in patients who were admitted to hospital for severe COVID-19 pneumonia requiring oxygen therapy.	Prospective, open-label, interventional study	Data was collected from 69 patients with severe COVID-19 pneumonia treated with either anakinra (n = 45) or from a historical control group (n = 24)	Complete	A need for mechanical ventilation occurred in 14 (31%) of the anakinra-treated group and 18 (75%) of the historical cohort (P < 0.001). In-hospital death occurred in 13 (29%) of the anakinra-treated group and 11 (46%) of the historical cohort (P = 0.082). Patients who received anakinra showed a significant reduction in inflammatory biomarkers.	Small sample size, lack of randomization could have caused bias, controlled group had non standardised treatment, leading to many confounding variables.